Reverse transcription is a common feature of retrovirus replication. Viral replication requires a virally encoded reverse transcriptase to generate DNA copies of viral sequences by reverse transcription of the viral RNA genome. Reverse transcriptase, therefore, is a clinically relevant target for the chemotherapy of retroviral infections because the inhibition of virally encoded reverse transcriptase would interrupt viral replication.
A number of compounds are effective in the treatment the human immunodeficiency virus (HIV) which is the retrovirus that causes progressive destruction of the human immune system with the resultant onset of AIDS. Effective treatment through inhibition of HIV reverse transcriptase is known for both nucleoside based inhibitors, such as azidothymidine, and non-nucleoside based inhibitors. Benzoxazinones have been found to be useful non-nucleoside based inhibitors of HIV reverse transcriptase. The (S)-6-chloro-4-cyclopropylethynyl-4-trifluoromethyl-1,4-dihydro-2H-3,1-ben zoxazin-2-one of formula (VI): ##STR1##
is not only a highly potent reverse transcriptase inhibitor, it is also efficacious against HIV reverse transcriptase resistance. Due to the importance of (S)-6-chloro-4-cyclopropylethynyl-4-trifluoromethyl-1,4-dihydro-2H-3,1-ben zoxazin-2-one as a reverse transcriptase inhibitor, economical and efficient synthetic processes for its production need to be developed.
Cyclopropylacetylene is an important reagent in the synthesis of compound (VI). Thompson et al, Tetrahedron Letters 1995, 36, 937-940, describe the asymmetric synthesis of an enantiomeric benzoxazinone by a highly enantioselective acetylide addition followed by cyclization with a condensing agent to form the benzoxazinone shown below. As a reagent the cyclopropylacetylene was synthesized in a 65% yield by cyclization of 5-chloropentyne with n-butyllithiun at 0.degree.-80.degree. C. in cyclohexane followed by quenching with ammonium chloride. The process generates a low yield of cyclopropylacetylene which is not feasible for the large commercial process of a difficult to handle reagent. ##STR2##
Thompson et al, PCT International Patent Application Number WO 9622955 A1 describe an improved synthesis of cyclopropylacetylene useful in the synthesis of (S)-6-chloro-4-cyclopropylethynyl-4-trifluoromethyl-1,4-dihydro-2H-3,1-ben zoxazin-2-one. Application WO 9622955 A1 discloses methods which continue to be inefficient in the overall synthesis on a kilogram scale for which this invention makes significant improvements.
The chemical literature shows the majority of the cyclopropylacetylene preparations involve the conversion of cyclopropylmethyl ketone to cyclopropyl-acetylene via the following chemical scheme. The method will produce cyclopropylacetylene on small scale, &lt;1 kilogram, but is not amenable for bulk production, thus an alternative was developed. ##STR3##
The above methods for the synthesis of cyclopropylacetylene use combinations of toxic, difficult to handle reagents, relatively expensive materials, incomplete conversions and low yields which render the overall synthesis inefficient and yield cyclopropylacetylene of lower purity. Thus, it is desirable to discover new synthetic routes to cyclopropylacetylene on a large scale which improve upon these limitations and provide high yields of desired cyclopropylacetylene.
The present invention discloses a novel scalable procedure for the preparation of substituted acetylenes, more specifically cyclopropylacetylene. Improvements over previously disclosed preparations of cyclopropyl acetylene are in the low economic price and availability of the starting materials; the convenience and high yields for the chemistry; and the ability to crystallize and store without degradation the intermediates. The invention provides novel chemistry for the production of cyclopropyl acetylene from cyclopropane carboxaldehyde. The process provides a high yield (&gt;90%) for the convenient reaction of cyclopropane carboxaldehyde with trichloroacetic acid to give 1,1,1-trichloro-2-cyclopropylethanol. The subsequent transformation of 1,1,1-trichloro-2-cyclopropylethanol to 1,1,1-trichloro-2-cyclopropyl-2-ethanyltosylate occurs in high yield using convenient reaction conditions. The final preparation of cyclopropylacetylene by dehalogenation from 1,1,1-trichloro-2-cyclopropyl-2-ethanyltosylate proceeds in high yields and with suitable purities so that the cyclopropyl acetylene produced and isolated can be stored or used as a solution in an inert solvent.
None of the above-cited references describe the methods of the present invention for the synthesis of substituted acetylenes, in particular, cyclopropylacetylene.